Bariatric surgery has become the treatment of choice for extreme obesity and is increasingly also considered for the treatment of adolescent and even childhood obesity and diabetes in non-obese patients. The success rate in shedding body fat and curing diabetes, hypertension, and sleep disturbances is very high and the risk is minimal given the new laparoscopic procedures. Thus, bariatric surgery, particularly Roux-en-Y gastric bypass surgery (RYGB) is presently the most effective treatment of obesity and its comorbidities. And yet, little is known regarding the physiological mechanisms involved. RYGB changes many aspects of energy balance, including energy assimilation, partitioning, and expenditure, but decreased caloric intake and alterations in eating behavior appear to be the most important. We propose to use a rat model to elucidate the hormonal and neural mechanisms leading to altered eating behavior and decreased food intake and body weight after RYGB surgery. Our overarching hypothesis assumes that RYGB-induced changes in signals from the gut impinge on specific brain systems involved in the controls of food intake and regulation of energy balance, and we propose three aims to test specific aspects of this assumption. In the first Specific Aim, we will determine the role of the caudal brainstem in RYGB-induced hypophagia and weight loss, because this part of the brain is directly connected with the gut by the vagus nerve and intimately involved in the control of satiation and meal size. In the second Specific Aim, we will focus on the hypothalamic circuitry that potently controls metabolic need-driven food intake and is thought to be responsible for long-term energy balance. In the third Specific Aim, we will assess the role of cortico-limbic systems thought to control the hedonic, cognitive, and emotional aspects of eating. In each aim, we will identify effects of RYGB on specific behaviors and neuronal activation patterns, and correlate this with changes in circulating hormone levels. We will also use interventional approaches by selectively interrupting specific signaling pathways including vagal afferents, PYY(3-36), GLP-1, and ghrelin, in the periphery and centrally, in order to rescue the abnormal eating phenotype after RYGB. Insight into how RYGB decreases food intake is important for several reasons, i.e., refinement of the surgical procedure, behavioral management of patients, and development of pharmacological treatments that mimic the surgery-induced effects. PUBLIC HEALTH RELEVANCE: Gastric bypass surgery has been shown to effectively treat severe obesity and cure type-2 diabetes often associated with obesity. People with gastric bypass surgery report they are just not as hungry and preoccupied with thoughts about food as before. Here we propose to investigate the physiological mechanisms leading to these beneficial changes in eating behavior in a rat model of gastric bypass surgery. This will result in more optimal surgical procedures, behavioral tips helping patients to cope with different eating habits, and development of new drugs.